Practice Update: Haematology & Oncology

VOL. 1 • No. 2 • 2016

RESEARCH NEWS AND VIEWS FROM ELSEVIER

FORMERLY HAEMATOLOGY & ONCOLOGY NEWS

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Undetermined: Whether lung cancer patients with autoimmune disease are candidates for immunotherapy

OPINION

There are a number of other small molecules that have been tested in CLL. We’ll see as we combine some of these small molecules if potentially we could shy away from chemotherapy in that disease. DR ANDRE GOY 10

COLON ESMO has released new consensus guidelines for the management of metastatic colorectal cancer that reflect an increasingly personalised approach to treatment.

Given the promise of cancer immunotherapy and the wide

prevalence of autoimmune diagnoses among lung cancer patients, research to determine whether these patients are candidates for such treatment is warranted. This conclusion, based on results of a database quantification of lung cancer patients with autoimmune conditions was presented at the 2016 Annual Meeting of the American Society of Clinical Oncology, from June 3–7.

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LUNG First-line therapy with

nivolumab plus ipilimumab has demonstrated clinical activity and manageable safety in advanced non-small-cell lung cancer in the phase 1 CheckMate 012 trial, results reported at ASCO show.

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CONFERENCE ASCO 2016

A genomic classifier leads to better decision making about salvage radiotherapy for local prostate cancer recurrence. Double stem cell transplant improves outcomes for children with high-risk neuroblastoma. Image-guided thermal ablation is proven safe and effective in T1a renal cell carcinoma.

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Angiotensin II antagonist treatment with candesartan in patients with early breast cancer JAMA Oncology The results of the study suggest that the use of candesartan does not protect against trastuzumab-related cardiotoxic effects.

Outcome according to KRAS-, NRAS-, BRAF-, and KRAS variant mutations in metastatic colorectal cancer Annals of Oncology In patients with metastatic colorectal cancer, mutations in KRAS and BRAF are associated with shorter PFS and OS.

Lenalidomide plus dexamethasone vs observation in patients with high-risk smoldering multiple myeloma The Lancet Oncology Early treatment with Rd in selected high- risk SMM patients offers TTP benefit, arguing against observation alone in this population. 10

Inotuzumab ozogamicin for acute lymphoblastic leukaemia The New England Journal of Medicine Inotuzumab ozogamicin therapy was superior to standard therapy in patients with acute lymphoblastic leukaemia;

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however, there was a higher risk of veno-occlusive liver disease associated with it.

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EXPERT OPINION Combating “financial toxicity”: HER2 biosimilars and combinations with chemotherapy By Dr Lee Schwartzberg Dr Lee Schwartzberg comments on a couple of trials presented at this year’s ASCO meeting in the context of combination treatment in metastatic HER2 breast cancer and, extrapolating on that, on the cost of cancer drugs and the emergence of biosimilars. P HEREXA was a randomised trial looking at the addition of a drug called pertuzumab. 1

EDITORIAL Managing Editor Anne Neilson anne.neilson@elsevier.com Editor Carolyn Ng carolyn.ng@elsevier.com Designer Jana Sokolovskaja j.sokolovskaja@elsevier.com Medical Advisor Dr Barry M Dale Consultant Haematologist, Medical Oncologist

with regard to response rates, with regard to safety. 2 We really haven’t seen any difference in this study so far. References 1. Urruticoechea A, Rizwanullah M, Im S-A, et al. Paper presented at 2016 annual meeting of the American Society of Clinical Oncology; Abstract 504. 2. Rugo HS, Barve A, Waller CF, et al. Paper presented at 2016 annual meeting of the American Society of Clinical Oncol- ogy; Abstract LBA503.

SALES Commercial Manager Fleur Gill fleur.gill@elsevier.com Account Manager Stephen Yue s.yue@elsevier.com

biosimilar is a drug. Unlike a small molecule, a biological is manufac- tured usually in a living system, be it cells or bacteria, and it’s not easy to make the same type of drug. So, biosimilars, which are biologicals that are made and look similar to the parent compound, although they may differ a little in manufacturing, comprise a new class of agents. The FDA has just put out the guidance and approved the first biosimilars in oncology; before this, we had a com- plicated problem. Now, we’re going to see a lot of biosimilars for all of the biologicals that we use, and, of course, in oncology, there are many biologicals that are used across many different disciplines. In breast cancer, trastuzumab is commonly used. It is the standard drug used in HER2-positive breast cancer, whether in the early-disease setting or the late-disease setting. It’s the go-to drug. Now we have biosimilars, and a phase III study presented at ASCO showed that the first biosimilar seemed to perform virtually identically to trastuzumab age range, 25–69 years) and 103 in the placebo group (mean age, 50 years; age range, 30–67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, −7% to 15%; P=0.58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13–0.40) in the candesartan group and 0.16 (95% CI, 0.08–0.22) in the placebo group (P = 0.56). Candesartan did not affect changes in NT-proBNP and hs-TnT val- ues, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/ Pro + Ala/Pro genotypes in multivari- ate analysis (odds ratio, 0.09; 95% CI, 0.02–0.45; P=0.003). CONCLUSIONS AND RELEVANCE The find- ings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects. Angiotensin II-receptor inhibition with candesartan to prevent trastu- zumab-related cardiotoxic effects in patients with early breast cancer

However, numerically, there was an improvement of a couple of months in progression-free survival. There was improvement of several months in overall survival with the addition of pertuzumab, although, again, based on the way the statistics were designed for this trial, it didn’t meet the endpoint. So, from a statistical perspective and a regulatory per- spective, the study didn’t meet its endpoint. From a clinical perspec- tive, I think it gives some weight to the possibility that, if we don’t use pertuzumab in the first-line setting, there could be benefit in the second- line setting for sure – it makes sense that, as a drug which adds to the anti-HER2 effect, it might have benefit there. Then, we have, as everyone is aware, an issue of financial toxicity in oncology. Drugs are very expensive, and they are getting more expensive. Combinations are coming. We have many wonderful innovations in on- cology, but the problem is that they cost a lot. One way to do something about it, is to make a biosimilar. A

Pertuzumab is an anti-HER2 an- tibody, and it has been shown to have great benefit in the first-line setting of metastatic breast cancer. When used in the first line-setting, it extends survival substantially when added to trastuzumab, the standard drug, plus a taxane. So, the stand- ard now in first-line setting is for patients to get a taxane, pertuzumab, and trastuzumab. However, not all patients get pertuzumab in the first-line setting, and so PHEREXA looked at how well will it perform in the second-line setting with trastu- zumab and another chemotherapy agent, capecitabine. These were all patients who received trastuzumab and a taxane first-line, and who were then randomised to get capecitabine, pertuzumab, and trastuzumab or just the trastuzumab and capecitabine without the pertuzumab. The study did not meet its primary endpoint, which was an improve- ment in progression-free survival.

DISCLAIMER PracticeUpdate Haematology&Oncology provides highlights of the key local and in- ternational conference events providing the specialist with timely relevant news, expert opinion and journal article reviews. The ideas and opinions expressed in this publication do not necessarily reflect those of the Publisher. Elsevier Australia will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Please consult the full current Product Information before prescribing any medicationmentioned in this publication. For an annual print and/or digital subscription (6 issues) of PracticeUpdate Haematology & Oncology , please email news.au@elsevier. com or visit elseviermedcomms.com.au To share your feedback with us, please email news.au@elsevier.com Conference news, expert opinion and journal scan articles are sourced from PracticeUp- date.com PracticeUpdate.com provides professional research, expert insight, and education re- sources in a single online destination. PracticeUpdate content is selected bymedical experts in oncology for its relevance, timeli- ness, and importance. It is guided by world- renowned editorial and advisory boards that represents community practitioners and academic specialists with cross-disciplinary expertise. For in-depth insights which matter, discover PracticeUpdate.com today. ISSN – 2206-463X (Print) ISSN – 2206-4648 (Online)

Dr Schwartzberg is Medical Director of the

West Clinic in Memphis, Tennessee, and Editor-in-Chief of PracticeUpdate Oncology.

New drugs and devices listing THERAPEUTIC GOODS ADMINISTRATION (TGA) www.tga.gov.au Emtricitabine/tenofovir alafenamide (Descovy) , Gilead Sciences – HIV-1 infection Progesterone (Prometrium) , Besins Healthcare – Menstrual abnormalities or secondary amenorrhoea, hormone replacement therapy Bimatoprost (Latisse) , Allergan – HER2-positive breast cancer Ulipristal acetate (Esmya) , ERA Consulting – Symptoms of uterine fibroids Perampanel (Fycompa) , Eisai – Primary generalised tonic-clonic seizures Secukinumab (Cosentyx) , Novartis – Psoriatic arthritis, ankylosing spondylitis PHARMACEUTICAL BENEFITS SCHEME www.pbs.gov.au Trastuzumab (Herceptin SC) , Roche – Breast cancer Enhancing eyelash growth Terlipressin (Glypressin) , Ferring Pharmaceuticals – Hepatorenal syndrome type 1 Pertuzumab (Perjeta) , Roche –

Editor’s pick JOURNAL SCAN Angiotensin II antagonist treatment with candesartan in patients with early breast cancer JAMA Oncology Take-home message • This was a randomised, placebo-controlled trial designed to assess whether treatment with the angiotensin II antagonist candesartan would decrease the risk of trastuzumab-related cardiotoxicity in 210 women with early-stage, HER2-positive breast cancer. Treatment with candesartan did not result in decreased rates of cardiotoxicity (20 events in candesartan group vs 16 events in placebo group). • The results of the study suggest that the use of candesartan does not protect against trastuzumab-related cardiotoxic effects; however, this study was limited in size, indicating the need for larger studies in the future. Dr Jeremy Jones

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INTERVENTIONS A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment. MAIN OUTCOMES AND MEASURES The primary outcome was LVEF. Second- ary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2(formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects. RESULTS A total of 206 participants were evaluable (mean age, 49 years; age range, 25–69 years) 103 in the can- desartan group (mean age, 50 years;

IMPORTANCE This is the first randomised placebo-controlled evaluation of a medi- cal intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE To determine as the primary end point whether angiotensin II an- tagonist treatment with candesartan can prevent or ameliorate trastuzumab- related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a de- crease below the absolute value 45%. DESIGN This randomised, placebo-con- trolled clinical study was conducted be- tweenOctober 2007 andOctober 2011 in 19 hospitals in the Netherlands, enrolling 210women with early breast cancer test- ing positive for human epidermal growth factor receptor 2 (HER2) who were be- ing considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.

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JAMA Oncol 2016 Jun 23;[EPub Ahead of Print], AH Boekhout, JA Gietema, BM Kerklaan, et al

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VOL. 1 • No. 2 • 2016

BREAST

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EXPERT OPINION DR KIMBERLEY BLACKWELL New data and new drugs for metastatic breast cancer: Recommendations by patient subtype

References 1. Finn RS, Martin M, Rugo HS, et al. Paper presented at: 2016 Annual Meeting of the American Society of Clinical Oncol- ogy 2016; Abstract 507. 2. MONALEESA-2 trial of Novartis’ LEE011 (ribociclib) stopped due to positive ef- ficacy results at interim analysis in HR+/ HER2- advanced breast cancer [press release]. Basel, Switzerland: Novartis; May 18, 2016. 3. Dickler MN, Tolaney SM, Rugo HS, et al. Paper presented at: 2016 Annual Meet- ing of the American Society of Clinical Oncology 2016; Abstract 510.

Dr Farzanna Haffizulla of PracticeUpdate speaks with Dr Kimberly Blackwell, Professor of Medicine and Assistant Professor of Radiation Oncology at Duke University, on what’s new in metastatic breast cancer.

Dr Haffizulla: Treatment and ER-pos- itive cancer in the advance setting, and for whom should palbociclib be considered? Dr Blackwell: Well, at least in my opinion, the near doubling in PFS when you layer palbociclib on top of endocrine therapy is really im- portant. 1 Although we have, to date, not seen a survival benefit for adding palbociclib to either fulvestrant or an aromatase inhibitor, most of us would consider a doubling in disease control, as measured by PFS, pretty important for patients. This means somewhere between a 4- to 6-month delay in needing another therapy. And I think that the side effects of palbociclib are fairly manageable; you have to watch the white counts, but, other than that, I think to dou- ble the progression-free survival on top of what you were going to give the patient anyway is meaningful. In

certainly a large enough study that, if the PFS is meaningful, we should see an overall survival benefit out of PALOMA-2. Dr Haffizulla: Where do you think the next set of advances in the adjuvant treatment of hormone receptor- positive cancers will be? Dr Blackwell: You know, that’s a tough population of patients because we do such a good job of curing them of their breast cancer that it’s hard to layer things on. So, there are three ongoing studies that I’m encourag- ing my patients to participate in. First, for BRCA-mutation carriers, we have a study randomising to a PARP inhibitor, olaparib versus control; so that would make sense. You’d finish your endocrine therapy, and you’re a BRCA carrier, maybe you would participate in that study. For other ER-positive early-stage breast cancer patients, we have two other studies. We have a study randomising everolimus in addition to antiestrogen therapy versus no everolimus; that’s a large adjuvant study. And then the third one is ac- tually evaluating palbociclib versus no palbociclib in addition to an ad- juvant endocrine regimen. These are actually three very important studies in which patients could participate. Obviously we’re not going to see the data for a couple of years, but those are the studies that I’m particularly interested in.

We are quickly getting to the point where it’s not “whether or not” someone should get a CDK inhibitor, but “which one do we use?”

Dr Haffizulla: It’s nice to have choices though, right? Dr Blackwell: Yes. Although a little confusing. Dr Haffizulla: Of course. We have to wait for some more data. And how long do you think before we see overall survival data? Dr Blackwell: Well, at this year’s ASCO, PALOMA-2 is being pre- sented, 1 and we expect to see, based on the press release, that it met its progression-free survival endpoint. Usually, once we see a PFS end- point, it’s a year or two before we see an overall survival benefit. It’s

my practice, I tend to recommend it for everyone. A recent press release indicates that the Novartis CDK inhibitor (riboci- clib), when combined with letrozole also has met its endpoint. 2 Then, at this year’s meeting, we had data about abemaciclib, which is a single agent. 3 Abemaciclib is a Lilly com- pound that’s also a CDK4/6 inhibi- tor. So, I think that we are quickly getting to the point where it’s not “whether or not” someone should get a CDK inhibitor, but “which one do we use?” It will be interesting to see how all of the studies pan out.

Dr Blackwell is the director of the Duke University

breast cancer group. She has been the principle investigator on over 40 clinical trials in

metastatic breast cancer, and the co-investigator on multiple large correlative science projects. She was the principle investigator on the pre-clinical, phase 2, and phase 3 studies that led to the approval of lapatinib for the treatment of HER2 overexpressing breast cancer.

JOURNAL SCAN Self-administered acupressure for persistent cancer-related fatigue in breast cancer survivors JAMA Oncology Take-home message • “This was a randomised, single-blinded, phase III trial designed to investigate if self-administered acupressure (relaxing or stimulating acupressure) improved fatigue, sleep, and quality of life in 288 survivors of stages 0 to III breast cancer. Both relaxing and stimulating acupressure routines were associated with significantly smaller fatigue inventory scores compared with usual care. Normal fatigue levels were achieved in 60.9% and 66.2% of stimulating and relaxing acupressure participants, respectively, compared with 31.3% of participants receiving usual care. Only relaxing acupressure resulted in significant improvements in sleep quality and overall quality of life.” • Persistent fatigue in breast cancer survivors can be alleviated by either relaxing or stimulating acupressure. Dr Jeremy C. Jones

Dr Farzanna Haffizulla

practices general internal medicine in Davie, Florida and was National President of the American Medical Women’s Association, 2014–2015.

5-Year extended adjuvant aromatase inhibition

Expert Comment It’s very refreshing and important to be conducting evidence- based research in the complementary medicine arena. These results are worth telling patients undergoing treatment and those who have recently completed acute treatment. Also important is to remind patients that, because a “treatment” doesn’t require a prescription, it doesn’t guarantee its safety, and all patients should discuss their interest in wanting to try complementary medicine therapies. It is particularly advis- able to focus on those therapies that have been studied in accurately performed evidence-based trials as this increases their credibility and an oncologist’s willingness for a patient to try them. We need to discourage patients from falling into a trap of watching commercials on TV or reading ads, the inten- tion of which may be to make money and not really provide patients the clinical care they need, rely on, and deserve. Lillie Shockney, RN, BS, MAS, who’s an expert in breast cancer treatment. Ms Shockney is Administrative Director of the Johns Hopkins Breast Center and Cancer Survivorship Programs. Abstract IMPORTANCE Fatigue is a common and debilitating late-term effect of breast cancer that is associated with poor sleep and decreased quality of life, yet therapies remain limited. Acupressure has reduced fatigue in previous small studies, but rigorous clinical trials are needed. OBJECTIVES To investigate if 6 weeks of 2 types of self-admin- istered acupressure improved fatigue, sleep, and quality of life vs usual care in breast cancer survivors and to determine if changes were sustained during a 4-week washout period. DESIGN, SETTING, AND PARTICIPANTS Phase 3 randomised, sin- gle-blind, clinical trial conducted from March 1, 2011, through October 31, 2014. Women were recruited from the Michigan Tumor Registry.

INTERVENTIONS Randomisation (1:1:1) to 6 weeks of daily self- administered relaxing acupressure, stimulating acupressure, or usual care. MAIN OUTCOMES AND MEASURES The primary outcome was change in the Brief Fatigue Inventory score from baseline to weeks 6 and 10. Secondary analyses were sleep (Pittsburgh Sleep Quality Index) and quality of life (Long-Term Quality of Life Instrument). RESULTS A total of 424 survivors of stages 0 to III breast cancer who had completed cancer treatments at least 12months previ- ously were screened, and 288 were randomised, with 270 receiving relaxing acupressure (n  =  94), stimulating acupres- sure (n = 90), or usual care (n  = 86). One woman withdrew owing to bruising at the acupoints. At week 6, the percent- ages of participants who achieved normal fatigue levels (Brief Fatigue Inventory score < 4) were 66.2% (49 of 74) in relaxing acupressure, 60.9% (42 of 70) in stimulating acupressure, and 31.3% (26 of 84) in usual care. At week 10, a total of 56.3% (40 of 71) in relaxing acupressure, 60.9% (42 of 69) in stimulating acupressure, and 30.1% (25 of 83) in usual care continued to have normal fatigue. At neither time point were the 2 acupres- sure groups significantly different. Relaxing acupressure, but not stimulating acupressure, showed significant improvements in sleep quality compared with usual care at week 6, but not at week 10. Only relaxing acupressure significantly improved quality of life vs usual care at weeks 6 and 10. CONCLUSIONS AND RELEVANCE Both acupressure arms signifi- cantly reduced persistent fatigue compared with usual care, but only relaxing acupressure had significant effects on sleep quality and quality of life. Relaxing acupressure offers a pos- sible low-cost option for managing symptoms. Investigation of 2 types of self-administered acupressure for persistent cancer-related fatigue in breast cancer survivors: a randomized clinical trial. JAMA Oncol 2016 Jul 07;[EPub Ahead of Print], SM Zick, A Sen, GK Wyatt, et al.

INTERVIEW WITH DR LEE SCHWARTZBERG

Dr Lee Schwartzberg, Medical Director at the West Clinic in Mem- phis, Tennessee, discusses results of the randomised trial MA.17R.

Implications for treatment of oestrogen receptor mutations

INTERVIEW WITH DR KIMBERLEY L BLACKWELL

Dr Kimberley Blackwell, Profes- sor of Medicine and Assistant Professor in Radiation Oncology, Duke Department of Medicine in Durham, talks about the increasing

information being presented about oestrogen recep- tor mutations.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY

COLON & RECTUM

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NEWS ESMO releases new consensus guidelines on the management of metastatic colorectal cancer ESMO, the leading European professional organisation for medical oncology, has released new consensus guidelines for the management of metastatic colorectal cancer that reflect an increasingly personalised approach to treatment, as published online in Annals of Oncology .

JOURNAL SCAN Clinical outcome after oxaliplatin treatment in stage II/III colon cancer subtypes JAMA Oncology Take-home message • The benefit of adding oxaliplatin to fluorouracil plus leucovorin was assessed in molecular subtypes of colon cancer through secondary analysis of the rand- omized NSABP C-07 trial. Recurrence-free survival was significantly improved with oxaliplatin in patients with stage III disease with an enterocyte subtype, but this was not validated in an independent cohort. Patients with the stem-like subtype did not benefit fromoxaliplatin treatment and shared poor prognosis with patients having colorectal cancer subtype 3 or consensus molecular subtype 4. • Clinical trials testing experimental therapies may be appropriate for colorectal cancer patients with stem-like subtype tumours because the subtype is as- sociated with poor prognosis regardless of stage or chemotherapy treatment.

“Management of metastatic colorectal cancer is be- coming more complex, requiring a strategic approach and evidence-based patient selection for the best treat- ment options,” said chair of the ESMO Consensus Conference Professor Eric Van Cutsem, from the University Hospitals Gasthuisberg/Leuven and KU Leuven, Belgium. In December 2014, ESMO convened an inter- national consensus panel of experts with subgroups focusing on molecular pathology and biomarkers, local and ablative treatment and treatment of metastatic disease. The subsequent recommendations are based on a significant new body of clinical trial evidence and an advanced understanding of the role and impact of molecular selection. One of the major innovations in the guidelines is the development of a detailed therapeutic algorithm that takes into account the patient’s condition and fitness; therapeutic goals such as tumour shrinkage or slowing disease progression; and molecular markers. The guidelines also address questions such as the use of chemoembolization and radioembolisation, imaging, and surgical resection. Recommendations made by the consensus panel include RAS and BRAF mutation testing at diagnosis for all patients with metastatic colorectal cancer. The guidelines also note that there is now growing evidence for more frequent testing for MSI. Testing emerging biomarkers such as EGFR or HER2 is not recom- mended as routine for patient management. “Colon cancer management is making progress,

leading patients who can be cured though multidisci- plinary management of metastases, and to prolonged survival – up from 6 months to 30 months – in many patients,” said Professor Van Cutsem. This progress is also attributed to the use of com- bination chemotherapy and the development of novel second line agents including angiogenesis inhibitors, EGFR antibodies and new agents for chemorefractory disease such as regorafenib and trifluridine/tipiracil. This second set of ESMO consensus guidelines for metastatic colorectal guidelines – the first were published in 2012 – integrates with the 2014 ESMO Clinical Practice Guidelines on metastatic colorectal cancer, which will be updated for publication in 2017. Commenting on the guidelines, Dr Fotios Loupakis from the Ospedale Civile – Istituto Toscano Tumori and member of the ESMO Faculty for Gastro-Intesti- nal Tumors, said, “With these long awaited guidelines, the management of metastatic colorectal cancer of- ficially enters the personalised era, addressing the role of existing and emerging biomarkers and their role in the clinic.” “The new guidelines move from the clinically- defined historical categories – which were focused on the resectability of metastases, to a less sharp but more realistic assessment that gives more importance to additional elements, such as patient, tumour and treatment characteristics.”

IMPORTANCE Oxaliplatin added to fluo- rouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but mod- est absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit. OBJECTIVE To test our hypothesis that mo- lecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy. DESIGN, SETTING, AND PARTICIPANTS Par- ticipants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n=881) cohorts based on the order of tissue block submission. A re- estimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was ex- amined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods. INTERVENTIONS Fluorouracil plus leucov- orin with or without oxaliplatin. MAIN OUTCOMES AND MEASURES Percent recurrence-free survival. RESULTS Among 1729 patients, 744 (43%)

were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discov- ery cohort (hazard ratio, 0.22 [95% CI, 0.09–0.56]; P=0.001 [n=65]), no statisti- cally significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22–1.24]; P=0.14 [n=70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73–1.34]; P=0.96 [n=367]). Examination of the different subtyping methods shows that all 3 methods robustly identified patients with poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III. CONCLUSIONS AND RELEVANCE Patients with stemlike tumours may be appropri- ate for clinical trials testing experimental therapies because stemlike tumours were robustly identified and associated with a poor prognosis regardless of stage or chemotherapy regimen. The clinical utility of using subtyping for the identification of patients for treatment with oxaliplatin requires validation in independent clinical trial cohorts. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: sec- ondary analysis of NSABP C-07/NRG oncology randomised clinical trial. JAMA Oncol 2016 Jun 06;[EPub Ahead of Print], N Song, KL Pogue-Geile, PG Gavin, et al.

ESMO Press Commentary

JOURNAL SCAN Recommendations on controversial issues in the primary treatment of rectal cancer European Journal of Cancer Take-home message • Controversial issues related to the treatment of rectal cancer were discussed and voted on by a multidisciplinary international panel in the context of the second St. Gallen EORTC Gastrointestinal Cancer Conference. MRI or MRI plus endoscopic ultrasonography was recommended by the panel for staging modalities as mandatory, except for early T1 cancers with an option for local excision. In early tumours with low risk of recurrence, primary surgery with total mesorectal excision was recommended. For tumours of other stages, multimodal treatment was recommended. In cases where neoadjuvant therapy is indicated, long-course radiochemotherapy (RCT) was recommended over short-course radiotherapy except for T3a/b N0 tumours. Preoperative short-course radiotherapy with combination chemotherapy or a liver-first resection was recommended for potentially resect- able tumours with coincident liver metastases instead of beginning with fluoropyrimidine-based RCT. • Treatment decisions for rectal cancer rely on critical pretreatment staging and range from local excision to radiochemotherapy in combination with more extensive resection.

JOURNAL SCAN Outcome according to KRAS-, NRAS-, BRAF-, and KRAS variant mutations inmetastatic colorectal cancer Annals of Oncology Take-home message • This study sought to analyse the outcomes of KRAS, NRAS, BRAF, and KRAS variant mutations in 1239 patients with metastatic colorectal cancer. Mutations in KRAS and BRAF were associated with shorter progression-free survival (PFS) and overall survival (OS) compared with non-mutated tumours. Further- more, KRAS G12C and G13D variants were associated with shorter survival. • In patients with metastatic colorectal cancer, mutations in KRAS and BRAF are associated with shorter PFS and OS.

unmutated tumours (multivariate HR 2.26 (1.25–4.1), P = 0.001). A similar trend for OS was seen in the KRAS G13D-variant (n=71, multivariate HR 1.46 (0.96–2.22), P = 0.10). More frequent KRAS exon 2 variants like G12D (n = 152, multivariate HR 1.17 (0.86– 1.6), P = 0.81) and G12V (n = 92, multivariate HR 1.27 (0.87–1.86), P =0.57) did not have significant impact on OS. CONCLUSION Mutations in KRAS, and BRAF were associated with inferior PFS and OS of mCRC patients compared to patients with non-mutated tumours. KRAS exon 2 mutation variants were as- sociated with heterogeneous outcome compared to unmutated tumours with KRAS G12C and G13D (trend) being as- sociated with rather poor survival. Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants – pooled analysis of five randomised trials in metastatic colorectal cancer by the AIO Colorec- tal Cancer Study Group. Ann Oncol 2016 Jun 29;[EPub ahead of print], Modest DP, Ricard I, Heinemann V, et al.

BACKGROUND To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with mCRC receiving first-line therapy. PATIENTS AND METHODS 1239 pts. from five randomised trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by Kaplan-Meier method, log rank tests and Cox models. RESULTS In 664 tumours no mutation was detected, 462 tumours were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free (PFS) and overall survival (OS) (multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P<0.001). BRAFmuta- tion was also associated with inferior PFS (multivariateHR: 2.19 (1.59–3.02), P < 0.001) and OS (multivariate HR: 2.99 (2.10–4.25), P < 0.001). Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared to

N0 with clear mesorectal fascia on MRI and clearly above the levator muscles), whereas all other stages were considered for multimodal treatment. The consensus panel recom- mended long-course RCT over short-course radiotherapy for most clinical situations where neoadjuvant treatment is indicated, with the exception of T3a/b N0 tumours where short-course radiotherapy or even no neoadjuvant therapy were regarded to be an option. In patients with potentially resectable tumours and synchronous liver metastases, most panel members did not see an indication to start with classi- cal fluoropyrimidine-based RCT but rather favoured preop- erative short-course radiotherapy with systemic combination chemotherapy or alternatively a liver-first resection approach in resectable metastases, which both allow optimal systemic therapy for the metastatic disease. In general, proper patient selection and discussion in an experienced multidisciplinary team was considered as crucial component of care. Second St. Gallen European Organisation for Research and Treatment of Cancer Gastrointestinal Cancer Conference: Consensus recommendations on contro- versial issues in the primary treatment of rectal cancer. Eur J Cancer 2016 Aug 01;63(xx)11-24, Lutz MP, Zalcberg JR, Glynne-Jones R, et al.

Primary treatment of rectal cancer was the focus of the second St. Gallen European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Cancer Conference. In the context of the conference, a multidisci- plinary international expert panel discussed and voted on controversial issues which could not be easily answered using published evidence. Main topics included optimal pretherapeutic imaging, indication and type of neoadjuvant treatment, and the treatment strategies in advanced tumours. Here we report the key recommendations and summarise the related evidence. The treatment strategy for localised rectal cancer varies from local excision in early tumours to neoadjuvant radiochemotherapy (RCT) in combination with extended surgery in locally advanced disease. Optimal pretherapeutic staging is a key to any treatment decision. The panel recommendedmagnetic resonance imaging (MRI) or MRI + endoscopic ultrasonography (EUS) as mandatory staging modalities, except for early T1 cancers with an op- tion for local excision, where EUS in addition to MRI was considered to be most important because of its superior near-field resolution. Primary surgery with total mesorectal excision was recommended by most panellists for some early tumours with limited risk of recurrence (i.e. cT1-2 or cT3a

VOL. 1 • No. 2 • 2016

WARNING: IMMUNE-RELATED ADVERSE REACTIONS WITH OPDIVO AND YERVOY (IPILIMUMAB) COMBINATION THERAPY. Physicians should consult the YERVOY product information prior to initiation of OPDIVO in combination with YERVOY. It is recommended that the combination of OPDIVO and YERVOY should be administered and monitored under the supervision of physicians experienced with the use of immunotherapy in the treatment of unresectable or metastatic melanoma. More frequent, and more serious, immune-related adverse reactions are seen with OPDIVO and YERVOY combination therapy than with the use of single agent nivolumab or ipilimumab. OPDIVO and YERVOY combination therapy can cause a wide range of potentially life-threatening immune-related adverse reactions including pneumonitis, hepatitis, diarrhoea/colitis, rash, hypophysitis and thyroid dysfunction, as well as immune-related adverse reactions in other organ systems. Early diagnosis and appropriate management are essential to minimise life-threatening complications (see PRECAUTIONS, ADVERSE EFFECTS and DOSAGE & ADMINISTRATION). Please refer to the Approved Product Information before prescribing. The Product Information is available upon request from BMS Medical Information Department: 1800 067 567 or can be accessed at: http://www.medicines.org.au/files/bqpopdiv.pdf PBS Information: OPDIVO monotherapy. Authority required (STREAMLINED) for the treatment of patients with unresectable (Stage III) or metastatic (Stage IV) melanoma. Refer to PBS schedule for full authority information. OPDIVO, in combination with YERVOY is not listed on the PBS. OPDIVO is not listed on the PBS for locally advanced or metastatic squamous or non-squamous non-small cell lung cancer.

Now PBS listed as monotherapy for unresectable Stage III or Stage IV metastatic melanoma

START OPDIVO 1 st LINE for BRAF wild-type advancedmelanoma patients

START OPDIVO 2 nd LINE for BRAF mutation-positive advancedmelanoma patients

For further information, please contact your local BMS representative or visit www.pbs.gov.au for full PBS criteria.

NAME OF THE MEDICINE: OPDIVO ® (nivolumab). INDICATIONS: OPDIVO, as monotherapy is indicated for the treatment of patients with unresectable (Stage III) or metastatic (Stage IV) melanoma. OPDIVO, in combination with YERVOY (ipilimumab) is indicated for the treatment of patients with metastatic (Stage IV) melanoma with M1c disease or elevated lactic dehydrogenase (LDH). OPDIVO, as monotherapy is indicated for the treatment of locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after prior chemotherapy. OPDIVO, as monotherapy is indicated for the treatment of locally advanced or metastatic non squamous NSCLC with progression on or after prior chemotherapy. In patients with tumour EGFR or ALK genomic aberrations, OPDIVO should be used after progression on or after targeted therapy. CONTRAINDICATIONS: Hypersensitivity to the active substance or to any of the excipients. PRECAUTIONS: OPDIVO as monotherapy and administered in combination with YERVOY (ipilimumab) is associated with immune-related adverse reactions (irARs) including pneumonitis, colitis, hepatitis, nephritis, renal dysfunction, severe rash or skin reactions, (including rare cases of Steven-Johnson syndrome and fatal toxic epidermal necrolysis, some with fatal outcome), endocrinopathies and encephalitis. Caution in patients with autoimmune disease, immunosuppressive therapy, symptomatic interstitial lung disease, active brain metastases, moderate or severe hepatic impairment, or in patients who experienced a severe or life-threatening skin adverse reaction to prior immunostimulatory anti- cancer therapy. OPDIVO is not approved for combination with EGFR TKI use in NSCLC. Use in children below 18 years of age is not recommended. Pregnancy Category D. Refer to the Product Information (PI) for a complete list of precautions. INTERACTIONS WITH OTHER MEDICINES: OPDIVO is not metabolised by drug metabolising enzymes, therefore it is not expected to have pharmacokinetic-based interactions. ADVERSE EFFECTS: Most frequently reported adverse events ( ≥ 10%) for OPDIVO as monotherapy are fatigue, musculoskeletal pain, rash, diarrhoea, constipation, nausea, pruritis, vomiting, abdominal pain, oedema, dyspnoea, erythema, vitiligo, arthralgia, headache, peripheral neuropathy, upper respiratory tract infection, pyrexia, chest pain, cough, sleep disorder, dizziness and decreased appetite. Most frequently reported adverse events ( ≥ 10%) for OPDIVO administered in combination with YERVOY (ipilimumab) are fatigue, musculoskeletal pain, rash, diarrhoea, constipation, nausea, pruritis, vomiting, abdominal pain, chills, oedema, vitiligo, arthralgia, headache, hypophysitis, blurred vision, colitis, dehydration, dizziness, hypothyroidism, hyperthyroidism, sleep disorder, pneumonitis, pyrexia, dyspnoea, cough, decreased weight, upper respiratory tract infection and decreased appetite. Other irARs such as pancreatitis, uveitis, demyelination, autoimmune neuropathy, Guillain–Barré syndrome, hypopituitarism, myasthenic syndrome and encephalitis have also been reported in clinical trials with OPDIVO monotherapy. Other irARs such as pancreatitis, uveitis, Guillain–Barré syndrome, hypopituitarism, gastritis, sarcoidosis, duodenitis and encephalitis have also been reported in clinical trials with OPDIVO in combination with YERVOY (ipilimumab). Please refer to the PI for a full list of adverse events. DOSAGE AND ADMINISTRATION: Recommended dose of OPDIVO as monotherapy (unresectable or metastatic melanoma, squamous and non squamous NSCLC) is 3 mg/kg administered intravenously (IV) over 60 minutes every 2 weeks. Treatment should be continued as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. OPDIVO in combination with YERVOY (ipilimumab) (metastatic [Stage IV] melanoma with M1c disease or elevated LDH): Please review the full prescribing information for YERVOY (ipilimumab) prior to initiation of OPDIVO in combination with ipilimumab. The recommended dose of OPDIVO in the combination phase is 1mg/kg administered IV over 60 minutes every 3 weeks for the first 4 doses followed by ipilimumab 3mg/kg administered IV over 90 minutes. The recommended dose of OPDIVO in the single-agent phase is 3mg/kg as monotherapy administered IV over 60 minutes every 2 weeks. Continue treatment with OPDIVO as long as clinical benefit is observed or until treatment is no longer tolerated by the patient. Management of irARs may require withholding of a dose and initiation of corticosteroid or other immunosuppressive therapy or permanent discontinuation of OPDIVO therapy. When OPDIVO is administered in combination with YERVOY (ipilimumab), if either agent is withheld, the other agent should also be withheld. Please refer to the PI for further details. Prepared from the Approved Product Information dated April 2016.

© 2016 Bristol-Myers Squibb. OPDIVO ® is a registered trademark of Bristol-Myers Squibb Company. BMS Medical Information: 1800 067 567. Bristol-Myers Squibb Australia Pty Ltd, ABN 33 004 333 322, 4 Nexus Court, Mulgrave, VIC 3170. NIV/0341/04-16. Date of preparation: June 2016. BMSA0255

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EXPERT OPINION DR FRED HIRSCH Current concepts in anti- angiogenic therapy for non–small cell lung cancer Dr Haffizulla speaks with Dr Fred Hirsch, CEO of the International Association for the Study of Lung Cancer and Professor of Medicine at the University of Colorado in Denver, at ASCO.

NEWS First-line therapy with nivolumab + ipilimumab has demonstrated clinical activity and manageable safety in advanced non- small-cell lung cancer First-line therapy with nivolumab plus ipilimumab has demonstrated clinical activity and manageable safety in advanced non-small-cell lung cancer in the phase 1 CheckMate 012 trial, results reported at ASCO show. D r Scott Joseph Antonia, of the H. Lee Moffitt Cancer Center & Research Institute in Florida, explained that nivolumab + ipilimumab is approved for advanced melanoma and has demonstrated clinical activity and manageable safety in various solid tumours. CheckMate 012 is a phase 1 study of nivolumab monotherapy or combined with other therapies first line for advanced non-small-cell lung cancer. Dr Antonia and colleagues reported updated results, in- cluding tumour growth dynamic modelling, derived from nivolumab + ipilimumab dosing schedules with a view to optimising safety and permitting synergistic activity. One hundred forty-eight patients with any non-small-cell lung cancer histology received nivolumab + ipilimumab across four dose cohorts. The primary objective was safety. Secondary objectives were objective response rate (Response Evaluation Criteria in Solid Tumors v1.1) and 24-week progression-free survival rate. Exploratory endpoints were overall survival and efficacy by tu- mour programmed death ligand 1 (PD-L1) expression. The effect of nivolumab + ipilimumab dosing was assessed by tumour growth dynamic modelling generated using individual tumour assessments. Model-predicted tumour shrinkage at week 12 was compared across cohorts. Treatment-related adverse events and select treatment-related adverse events were manageable. Treatment-related adverse events leading to discontinuation were comparable to nivolumab alone (10%), with no treatment-related deaths. Across cohorts, objective response rates ranged from 13–39%. Median duration of response was not reached. Responses were noted regardless of PD-L1 expression, with a higher magnitude of benefit in tumours that expressed PD-L1. Tumour growth dynamic modelling predicted enhanced tumour shrinkage for nivolumab 3 mg per kilogram of body weight + ipili- mumab 1 mg/kg schedules compared with nivolumab alone or any nivolumab 1 mg/kg – containing schedule. Based on integrated efficacy, safety, and tumour growth dynamic data, nivolumab 3 mg/kg every 2 weeks + ipilimumab 1 mg/kg every 6 weeks was proposed for further evaluation. Dr Antonia concluded that first-line therapy with nivolumab + ipilimumab demonstrated clinical activity and a manageable safety profile.

Dr Haffizulla: Dr Hirsch, revisiting the idea of anti-angio- genic therapy in the adjuvant setting in lung cancer, what is your opinion of some of the data that were presented? Dr Hirsch: We saw the data from the large ECOG study with adjuvant chemotherapy and bevacizumab, and, in princi- ple, it is a negative trial. 1 The data were also presented at the IASLC World Conference on Lung Cancer last year in Denver. They have updated the data, but the update doesn’t change the main message. Angiogenesis in lung cancer is certainly a target. I think the problem is we don’t

have a biomarker. We have tried so hard to find a biomarker for bevacizumab, and for other anti-angiogenic drugs, but we haven’t succeeded. And I think selection of patients is important when we are talking personalised therapy. The adjuvant trial from ECOG – of course, it was disap- pointing to see a negative trial, but it tells us something. It tells us, among other things, that such a trial has gone on for years. I don’t know if it’s 8 years or 10 years to come to these results. We need to find mechanisms for doing trials much faster. We cannot wait 10 years. The

science goes so fast, so we need to move into smaller trials where we can evaluate signals. We need adaptive design like the ALCHE- MIST study, which is a targeted approach. Dr Haffizulla: Absolutely. Well, speaking about non-small cell lung cancer, I know that we spoke about anti-angiogenic therapy; how will this affect the treatment paradigm for non-small cell disease? Dr Hirsch: Well, bevacizumab was approved many years ago, and, of course, it’s introduced in clinical practice. It’s not used all the time in all places for several reasons; however, it is approved and it is in the guidelines. Other angiogenic drugs are also approved in second line; ramucirumab is also in this category. I think the whole problem with angiogenic treatment is that we haven’t succeeded in getting a selection paradigm. References 1. Wakelee HA, Dahlberg SE, Keller SM, et al. Paper presented at: 2016 Annual Meeting of the American Society of Clinical Oncology; Abstract 8507. T790Mwas detected in plasma of 18 (31%). ORR and median PFS were similar in pa- tients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumour (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M- negative plasma had overall favourable outcomes (ORR, 46%; median PFS, 8.2 months), tumour genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months). CONCLUSION In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study sug- gests that, upon availability of validated plasma T790M assays, some patients could avoid a tumour biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyp- ing, those with T790M-negative plasma results still need a tumour biopsy to de- termine presence or absence of T790M. Association between plasma genotyp- ing and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 2016 Jun 27;[Epub ahead of print], Oxnard GR, Thress KS, Alden RS, et al.

JOURNAL SCAN Plasma genotyping and outcomes with osimertinib treatment in patients with advanced NSCLC Journal of Clinical Oncology Take-home message • This retrospective study was designed to evaluate the efficacy of cell-free plasma DNA genotyping as a biomarker in predicting the outcome with osimer- tinib in patients with advanced non-small cell lung cancer. Objective response rates and progression-free survival of patients with T790M-positive plasma were similar to those with T790M-positive tumours (63% and 9.7 months vs 62% and 9.7 months, respectively). Additionally, tumour genotyping allowed for differentiation of T790M-positive plasma patients with better outcomes and T790M-negative plasma patients with poor outcomes with osimertinib. • The analysis allows for the possibility of replacing invasive tumour biopsy with noninvasive T790M genotyping Dr Jeremy Jones

PracticeUpdate Editorial Team

Key data fromASCO: Immunotherapy for lung cancer INTERVIEW WITH DR FRED HIRSCH Dr Fred Hirsch, CEO of the International Association for the Study of Lung Cancer and Professor of Medicine at the University of Colorado

Abstract PURPOSE Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrat- ed potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. METHODS Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included

had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAM- ing. Plasma genotyping accuracy was assessed by using tumour genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analysed in all T790M-positive or T790M- negative patients. RESULTS Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumours,

in Denver, talks about key research in immuno- therapy for lung cancer.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY